Critically, the link between AA availability and mTORC1 signaling is dependent upon FTO’s demethylase activity, although the question of how and why this occurs remains to be answered166. One possibility could involve FTO’s ability to demethylate 6meA. Using antibodies against 6meA to immunoprecipitate human and mouse transcripts that carry the modification and coupling this to RNA-seq, two recently published studies have mapped the presence of 6meA in a transcriptome-wide manner.168,169 6meAs, as it turns out, are common, enriched near stop-codons, highly conserved between mice and man, and are dynamically, developmentally and tissue specifically regulated. These studies have far reaching implications, as the decoration of 6meA at appropriate mRNA sites appears to play a fundamental regulatory role in gene expression, in addition to exerting varying effects on mRNA splicing and transport. To date, methyltransferase like 3 (METTL3) is the only enzyme identified to catalyse the conversion of adenosine to 6meA,170 while two enzymes are known to catalyse the removal of this methyl group; one is ALKBH5171 and the other is FTO. In fact, Meyer and colleagues show that transient overexpression of FTO in HEK293 cells decreases the total amount of 6meA found in the transcriptome169.
